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Viral Load Drives Disease in Humans Experimentally Infected with Respiratory Syncytial Virus

RATIONALE AND OBJECTIVE: Respiratory syncytial virus (RSV) is the leading cause of childhood lower respiratory infection, yet viable therapies are lacking. Two major challenges have stalled antiviral development: ethical difficulties performing pediatric proof-of-concept studies and the prevailing concept that disease is immune-mediated rather than being driven by viral load. We developed a human experimental wild-type RSV infection model to address these challenges. METHODS: Healthy volunteers (n = 35), in 5 cohorts, received increasing quantities (3.0 - 5.4 log PFU/person) of wild-type RSV-A intranasally. RESULTS: Overall, 77% of volunteers consistently shed virus. Infection rate, viral loads, disease severity and safety were similar between cohorts and were unrelated to quantity of RSV received. Symptoms began near the time of initial viral detection, peaked in severity near when viral load peaked, and subsided as viral loads (measured by RT-PCR) slowly declined. Viral loads correlated significantly with intranasal proinflammatory cytokine concentrations (IL-6, IL-8). Increased viral load correlated consistently with increases in multiple different disease measurements (symptoms, physical exam, amount of nasal mucus). CONCLUSION: Viral load appears to drive disease manifestations in humans with RSV infection. The observed parallel viral and disease kinetics support a potential clinical benefit of RSV antivirals. This reproducible model facilitates development of future RSV therapeutics. American Journal of Respiratory and Critical Care Medicine. 2010;doi:10.1164/rccm.201002-0221OC

Author: DeVincenzo JP, Wilkinson T, Vaishnaw A, Cehelsky J, Meyers R, Nochur S, Harrison L, Meeking P, Mann A, Moane E, Oxford J, Pareek R, Moore R, Walsh E, Studholme R, Dorsett P, Alvarez R, Lambkin-Williams R

Published: 01/01/2010

Publication Type: Journal article

Publisher: American Journal of Respiratory and Critical Care Medicine